PTEN protein negatively regulates cellular signals used in a wide variety of physiological processes. At the molecular level, PTEN is a phosphatase that destroys the second messenger phosphatidylinositol-3,4,5-triphosphate (Pl- 3,4,5-P) by removing a phosphate from the inositol ring. When PTEN is mutated, PI-3,4,5-P levels rise in the cell. PI-3 kinase proteins generate PI-3,4,5-P. PTEN and PI-3 kinase are key mediators of many cell surface receptors. Insulin is perhaps the best understood signal that utilizes PTEN and PI-3 kinase. T his highly conserved pathway employs the insulin receptor to stimulate PI-3 kinase. Elevated PI-3,4,5-P levels activate AKT kinase, which can phosphorylate the FOXO family members to attenuate their transcriptional activity. PTEN also regulates many other proteins in the cell and has been implicated in the control of the cell cycle, metabolism, cell growth, apoptosis, oxidation, and migration. Aberrant PTEN pathway signaling is associated with cancer, diabetes, and Parkinson's disease. Genetic alteration of the PTEN/PI-3 kinase pathway in cancer is extremely common and is an outstanding target for therapy. This meeting will comprehensively address topics of basic research, disease models, and therapeutic intervention for the ultimate purpose of improving patient care. This proposal seeks support for three successive biennial meetings to be held in 2006, 2008 and 2010.